Differential apoptosis and Fas expression on GPI‐negative and GPI‐positive stem cells: a mechanism for the evolution of paroxysmal nocturnal haemoglobinuria*

Abstract

Summary. Paroxysmal nocturnal haemoglobinuria (PNH) has a dual pathogenesis. PIG-A mutations generate clones of haemopoietic stem cells (HSC) lacking glycosylphosphatidylinositol (GPI)-anchored proteins and, secondly, these clones expand because of a selective advantage related to bone marrow failure. The first aspect has been elucidated in detail, but the mechanisms leading to clonal expansion are not well understood. We have previously shown that apoptosis and Fas expression in HSC play a role in bone marrow failure during aplastic anaemia. We have now investigated apoptosis in PNH. Ten patients were studied. Apoptosis, measured by flow cytometry, was significantly higher among CD34 + cells from patients compared with healthy controls. Fas expression was also increased. Cells that were stained for CD34, CD59 and apoptosis showed a significantly lower apoptosis in CD34 + /CD59 ) compared with CD34 + /CD59 + cells from the same patient. In three patients, staining for CD34, CD59 and Fas revealed lower Fas expression on CD34 + /CD59 ) cells. Differential apoptosis of CD34 + /CD59 ) HSC may be sufficient in itself to explain the expansion of PNH clones in the context of aplastic anaemia. In addition to demonstrating a basic mechanism underlying PNH clonal expansion, these results suggest further hypotheses for the evolution of PNH, based on the direct or indirect resistance of GPI-negative HSC to pro-inflammatory cytokines.

GPI-anchored protein-deficient T cells in patients with aplastic anemia and low-risk myelodysplastic syndrome: implications for the immunopathophysiology of bone marrow failure

“…Both the GPI‐AP − and GPI‐AP + T cells proliferated in response to anti‐CD3 and anti‐CD28 mAbs (Fig. 4B,C), though GPI‐AP − T cells tended to show greater proliferation than GPI‐AP + T cells in keeping with previous reports (29, 30). The addition of HVEM‐IgG inhibited the decline in the CFSE level of GPI‐AP + T cells more potently (27, 31, 32) than that of GPI‐AP − T cells (Fig.…”

How doPIG-Amutant paroxysmal nocturnal hemoglobinuria stem cells achieve clonal dominance?

“…Nevertheless, two of these studies concluded that since the degree of resistance was not proportional to PNH clone size the resistance may be independent of the PIG-A mutation [33,35]. Because primary GPI-AP-deficient CD34 + progenitors exhibited similar proliferative and survival rates to CD34 + progenitors from healthy controls, these studies concluded that the survival advantage of the GPI-AP-deficient cells resulted from diminished survival of GPI-AP + stem cells in a 'hostile' PNH environment [32,34,36]. However, it is possible that GPI-AP-deficient stem cells may also be damaged by the same hostile environment and an intrinsic survival advantage in PNH cells may be obscured when PNH progenitors are compared with normal control cells.…”

Paroxysmal Nocturnal Hemoglobinuria: Stem Cells and Clonality

“…35,37 Because primary GPI-AP-deficient CD34 + progenitors exhibited similar proliferative and survival rates to CD34 + progenitors from healthy controls, these studies concluded that the survival advantage of the GPI-AP-deficient cells resulted from diminished survival of GPI-AP + stem cells in a "hostile" PNH environment. 34,36,38 However, it is possible that GPI-AP-deficient stem cells may also be damaged by the same hostile environment, and an intrinsic survival advantage in PNH cells may be obscured when PNH progenitors are compared to normal control cells.…”